1. Field of the Invention
The present invention provides novel tetrazole compounds which are potent inhibitors of the enzmye 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, therefore, are useful in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The present invention also provides novel processes for the preparation of the tetrazole compounds and to certain intermediates in their preparation.
2. Disclosure Statement
The natural fermentation products Compactin (R.dbd.H) disclosed by A. Endo, et al. in Journal of Antibiotics, 29, 1346-1348 (1976) and Mevinolin (R.dbd.CH.sub.3) disclosed by A. W. Alberts, et al. in J. Proc. Natl. Acad. Sci. U.S.A., 77, 3957 (1980) are very active antihypercholesterolemic agents which limit cholesterol biosynthesis by inhibiting the enzyme HMG--CoA reductase, the rate-limiting enzyme and natural point of cholesterogenesis regulation in mammals, including man. Compactin (R.dbd.H) and Mevinolin (R.dbd.CH.sub.3 ; also known as lovastatin) have the structures shown below: ##STR4##
A number of structurally related synthetic compounds useful in the treatment of hypercholesterolemia have also been disclosed in patents and other publications. The synthetic art most closely related is as follows:
U.S. Pat. No. 4,198,425, issued Apr. 15, 1980 to S. Mistui, et al. describes novel mevalonolactone derivatives useful for the treatment of hyperlipidemia and having the general formula ##STR5## wherein A represents a direct linkage, methylene, ethylene, trimethylene or vinylene group and R.sup.3, R.sup.4 and R.sup.5 represent various substituents.
European patent application EP-24,348 published Mar. 4, 1981 discloses new hypocholesterolemic and hypolipemic compounds having the structure ##STR6## wherein A is H or methyl; E is a direct bond, --CH.sub.2 --, --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 -- or --CH.dbd.CH--; R.sup.1, R.sup.2 and R.sup.3 each represent various substituents and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring.
U.S. Pat. No. 4,375,475, issued Mar. 1, 1983 to A. K. Willard, et al. discloses essentially the same structures and is concordant to the above-mentioned EP-24,348 patent application.
European patent application EP-68,038 published Jan. 5, 1983 discloses and claims the resolved trans-enantiomer, process for its preparation and pharmaceutical composition thereof having the structure ##STR7## and the corresponding dihydroxy acid, or a pharmaceutically acceptable salt thereof.
International patent application WO 84/02131 published Jun. 7, 1984 describes analogs of mevalonolactone having the structure ##STR8## wherein: one of R and R.sup.0 is ##STR9## and the other is primary or secondary C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or phenyl--(CH.sub.2).sub.n --;
X is --(CH.sub.2).sub.n -- or --CH.dbd.CH--; PA1 n is 0, 1, 2 or 3; PA1 Z is ##STR10## and R.sup.4, R.sup.5, R.sup.5a and R.sup.6 represent various substituents. PA1 Z is ##STR15## wherein the dotted lines represent possible double bonds there being 0, 1, or 2 double bonds. PA1 R.sup.2, R.sup.3, R.sup.5 and R.sup.6 each are independently hydrogen, halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; PA1 tet is ##STR21## n is an integer of from 0 to 2, inclusive; A is ##STR22## R.sup.7 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy(lower)alkyl or (2-methoxyethoxy)methyl; PA1 X is --OH or .dbd.O, and PA1 R.sup.8 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt. PA1 R.sup.2, R.sup.3, R.sup.5 and R.sup.6 each are independently hydrogen, halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; PA1 n is an integer of from 0 to 2 inclusive; PA1 A is ##STR37## R.sup.7 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy(lower)alkyl or (2-methoxyethoxy)methyl; PA1 X is --OH or .dbd.O; and PA1 R.sup.8 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt.
International patent application WO 84/02903 published Aug. 2, 1984 describes mevalonolactone analogs having the structures ##STR11## wherein X is ##STR12## n=0, 1, 2, or 3 and both q's are 0 or one is 0 and the other is 1 and ##STR13##
European patent application EP-142,146 published May 22, 1985 describes oxo- analogs of mevinolin-like antihypercholesterolemic agents having the structure ##STR14## wherein E is --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH-- or --(CH.sub.2).sub.3 --; and
In J. Med. Chem., 28, 347-358 (1985), G. E. Stokker, et al. report the preparation and testing of a series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives.
In J. Med. Chem., 29, 159-169 (1986), W. F. Hoffman, et al. describe the preparation and testing of a series of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic (heptanoic) acids and their lactone derivatives. One of the preferred compounds in the reported series has the structure ##STR16##
In J. Med. Chem., 29, 170-181 (1986), G. E. Stokker, et al. report the synthesis of a series of 7-[3,5-disubstituted (1,1'-biphenyl)-2-yl]-3,5-dihydroxy-6-heptenoic acids and their lactones. Two of the preferred compounds reported in this article have the structures ##STR17##
U.S. Pat. No. 4,613,610, issued Sep. 23, 1986 to J. R. Wareing describes pyrazole analogs of mevalonolactone and its derivatives useful for the treatment of hyperlipoproteinemia and atherosclerosis and having the general formula ##STR18## wherein X is --(CH.sub.2).sub.n --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--; n is 0, 1, 2 or 3, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Z represent various substituents.
None of the cited patents and articles disclose or suggest the possibility of preparing the compounds of the present invention. The unique structural feature which incorporates a tetrazole moiety in the present compounds differs substantially from the cited art while exhibiting potent HMG-CoA activity.